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Synthesizing Ginsenoside Rh2 in Saccharomyces Cerevisiae Cell Wang et al. Cell Discovery (2019) 5:5 Cell Discovery DOI 10.1038/s41421-018-0075-5 www.nature.com/celldisc ARTICLE Open Access Synthesizing ginsenoside Rh2 in Saccharomyces cerevisiae cell factory at high-efficiency Pingping Wang1,WeiWei1,WeiYe2,3,XiaodongLi1,2, Wenfang Zhao1,ChengshuaiYang1,2, Chaojing Li1,2, Xing Yan1 and Zhihua Zhou1 Abstract Synthetic biology approach has been frequently applied to produce plant rare bioactive compounds in microbial cell factories by fermentation. However, to reach an ideal manufactural efficiency, it is necessary to optimize the microbial cell factories systemically by boosting sufficient carbon flux to the precursor synthesis and tuning the expression level and efficiency of key bioparts related to the synthetic pathway. We previously developed a yeast cell factory to produce ginsenoside Rh2 from glucose. However, the ginsenoside Rh2 yield was too low for commercialization due to the low supply of the ginsenoside aglycone protopanaxadiol (PPD) and poor performance of the key UDP- glycosyltransferase (UGT) (biopart UGTPg45) in the final step of the biosynthetic pathway. In the present study, we constructed a PPD-producing chassis via modular engineering of the mevalonic acid pathway and optimization of P450 expression levels. The new yeast chassis could produce 529.0 mg/L of PPD in shake flasks and 11.02 g/L in 10 L fed-batch fermentation. Based on this high PPD-producing chassis, we established a series of cell factories to produce ginsenoside Rh2, which we optimized by improving the C3–OH glycosylation efficiency. We increased the copy 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; number of UGTPg45, and engineered its promoter to increase expression levels. In addition, we screened for more efficient and compatible UGT bioparts from other plant species and mutants originating from the direct evolution of UGTPg45. Combining all engineered strategies, we built a yeast cell factory with the greatest ginsenoside Rh2 production reported to date, 179.3 mg/L in shake flasks and 2.25 g/L in 10 L fed-batch fermentation. The results set up a successful example for improving yeast cell factories to produce plant rare natural products, especially the glycosylated ones. Introduction microbial cell factories3,4, highlighting the potential for High-efficiency production of artemisinic acid via yeast metabolic engineering of microbial chassis to provide fermentation has become a milestone for the application reliable approaches for obtaining natural plant products of synthetic biology to the production of natural plant on a large scale, especially rare natural products. products1,2. Since then, a series of plant natural products Ginsenoside Rh2, derived from Panax species, is a pro- – have been successfully heterologously produced in mising candidate for cancer prevention and therapy5 7. However, the ginsenoside Rh2 accounts for less than 0.01% of dried Panax ginseng roots8. Commercially available gin- Correspondence: Xing Yan ([email protected]) or Zhihua Zhou senoside Rh2 is currently produced mainly via the ([email protected]) 1CAS-Key Laboratory of Synthetic Biology, CAS Center for Excellence in deglycosylation of major protopanaxadiol (PPD)-type gin- Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Shanghai senosides isolated from Panax spp. using chemical or bio- – Institutes for Biological Sciences, Chinese Academy of Sciences, 300 Fenglin Rd, transformation approaches9 11.However,suchapproaches Shanghai 200032, China 2University of Chinese Academy of Sciences, Beijing 100049, China rely heavily on the cultivation of Panax plants and the Full list of author information is available at the end of the article. © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Wang et al. Cell Discovery (2019) 5:5 Page 2 of 14 successive cultivation of Panax plants is unsustainable, convert PPD into ginsenoside Rh2 increased by more than resulting in low productivity and vulnerability to disease 1800-fold. The yeast cell factory with this engineered outbreaks12. A synthetic biology strategy to artificially pro- glycosyltransferase could produce ~300 mg/L of ginse- duce ginsenoside Rh2 from glucose in a metabolically noside Rh2 in a 5L fed-batch fermentation system. engineered microbial cell factory is expected. However, there are still many disadvantages of the use of PPD is the common precursor of all dammarane-type UGT from bacteria or yeast, such as its poor substrate ginsenosides, including ginsenoside Rh2. A key enzyme to specificity. For example, the engineered UGT51 can also glycosylate PPD to produce ginsenoside Rh2 is required. catalyze the C3–OH glycosylation of many native yeast A Korean research group reported the isolation of two sterols (e.g., ergosterol), and thus produce diverse by- glycosyltransferase (UGT) genes involved in the bio- products and waste UGT enzyme activity17. Meanwhile, synthesis of the ginsenosides Rh2 and Rg313. Nearly Bs-YjiC exhibits poor site specificity to C3–OH, resulting concurrently, we also characterized two UGTs (UGTPg45 in lower ginsenoside Rh2 yield (0.2 g/L) compared with and UGTPg29) taking parts in the biosynthesis of ginse- the high F12 yield (3.98 g/L)16. nosides Rh2 and Rg3 independently14. In this previous Besides, optimization of the PPD-producing chassis may work, we constructed the strain D20RH18 for de novo also improve ginsenoside Rh2 yield. In the past several production of ginsenoside Rh2 from glucose based on the years, much progress has been made in engineering PPD-producing chassis strain ZW-PPD-B (chassis 1.0, microbes for high-level production of PPD. For example, with a PPD titer of 75.3 mg/L in shake flasks)14. However, by integrating the PPD biosynthesis pathway into a yeast the ginsenoside Rh2 production of D20RH18 was rela- chromosome and overexpressing the rate-limiting gene tively low (16.95 mg/L in shake flasks), and the yield of tHMG1 (truncated HMG-CoA reductase gene) and three total dammarane-type triterpenoids (dammarenediol II key precursor genes, the resulting PPD-producing strain [DM], PPD, and ginsenoside Rh2) was also low. Kinetic could produce 148.1 mg/L PPD in shake flasks, and the analysis of the biopart UGTPg45 to produce ginsenoside titer reached more than 1 g/L in fed-batch fermentation18. Rh2 revealed a low catalytic efficiency, only 1/2500 of that Recently, to overcome the poor coupling between P. of UGTPg29, which further catalyzes ginsenoside Rh2 ginseng cytochrome P450 and the Arabidopsis thaliana into Rg3. Therefore, we reasoned that the limited supply cytochrome P450 reductase ATR1, as well as the high DM of the precursor for dammarane-type triterpenoid synth- accumulation in PPD-producing yeast recombinants, the esis and poor performance of the key UGT biopart were fusion of PPDS and ATR1 encoding genes was introduced the two key factors hindering the high-efficiency pro- and the PPD production increased significantly, reaching duction of ginsenoside Rh2. 265.7 mg/L PPD in shake flasks and 4.25 g/L in 5 L fed- Since the first two reports of the ginsenoside Rh2 bio- batch fermentation, which is the highest PPD production synthetic pathway, several studies have attempted to ever reported19,20. optimize this glycosylation step by identifying UGT bio- In this study, we constructed a new PPD-producing parts from microbial sources or by engineering UGTs to chassis strain to improve the conversion of glucose into catalyze ginsenoside Rh2 formation. UGTs from bacteria PPD by overexpressing all mevalonic acid (MVA) pathway often show substrate flexibility and are potential candi- genes and optimizing the expression levels of cytochrome dates for ginsenoside Rh2 synthesis. UGT109A1 from P450 enzymes in yeast. In addition, we employed several Bacillus subtilis could catalyze the C3–OH and C12–OH strategies to optimize the cell factories to produce gin- glycosylation of DM, PPD, and protopanaxatriol (PPT)15. senoside Rh2 by improving UGTPg45 expression level Another UGT from B. subtilis, Bs-YjiC, which shares 94% and activity, including: (1) increasing UGTPg45 expres- identity with UGT109A1, could also catalyze the C3–OH sion by increasing its copy number and engineering its and C12–OH glycosylation of PPD to yield ginsenoside promoter and (2) increasing the in vivo activity of Rh2 and an unnatural ginsenoside F12 (3-O-β-D-gluco- UGTPg45 in yeast via protein engineering based on pyranosyl-12-O-β-D-glucopyranosyl-20(S)-proto- in vivo directed evolution and searching for novel UGTs panaxadiol)16. Coupling this enzyme with a UDP-glucose with higher C3–OH glycosylation efficiencies from other regeneration system powered by sucrose synthase, an plant species. in vitro one-pot ginsenoside synthesis platform was established to produce 0.2 g/L of ginsenoside Rh2 and Results 3.98 g/L of F12 using PPD as the substrate16. Another Design and construction of the PPD-producing chassis group built an efficient ginsenoside Rh2 biosynthetic cell 2.0 strain factory by repurposing an inherently promiscuous UDP- Ten enzymes are required to synthesize the triterpenoid glycosyltransferase UGT51 from Saccharomyces cerevi- precursor 2, 3-oxidosqualene from acetyl coenzyme A siae17. Based on a structure-guided semi-rational engi- (acetyl-CoA) in the MVA pathway. Then three hetero- neering approach, the catalytic efficiency of UGT51 to logous genes from P.
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